Head and neck cancer poses significant treatment challenges due to high rates of recurrence after definitive therapy for locally advanced disease. Radiation therapy with concurrent cisplatin has been the standard of care for non-surgical management of head and neck cancer for the past 15 years, with no recent therapeutic advances to improve outcomes for head and neck cancer that is unrelated to human papillomavirus (HPV) infection. Preclinical models of HPV-negative head and neck cancer are critical to improve the understanding of the biology of these tumors to devise novel treatment strategies. Most currently available preclinical head and neck cancer models utilize xenografts in immunodeficient mice or syngeneic transplant tumor models, which have limited tumor heterogeneity and do not recapitulate gradual co-evolution of human tumors with an intact immune system. This lack of preclinical models that mimic human head and neck cancer development and metastasis represents a substantial barrier to studying tumor biology and discovering effective new therapies for this disease. To address this gap, the current proposal employs novel spatially and temporally restricted carcinogen-induced and genetically engineered mouse models of head and neck squamous cell carcinoma in immunocompetent mice to interrogate mechanisms of chemoradiation resistance and to assess novel therapeutic combinations with radiation therapy. The long-term goal of this research is to identify and test new approaches to improve radiation response and to reduce development of metastatic disease for head and neck cancer patients. In preparation for launching a successful independent research program, receipt of a K08 Award will facilitate credentialing these novel primary preclinical tumor models. Moreover, a K08 Award will provide the opportunity to acquire new knowledge and skill sets to study genetic alterations and epigenetic changes affecting tumor response and resistance to therapy. In addition, it will facilitate protected time for focused training in grant writing, laboratory management, and career development. The proposed research is innovative because it employs the first preclinical models with spatially and temporally restricted tumors induced by genetic mutations that are commonly identified in human head and neck cancer, along with exposure to a clinically relevant carcinogen present in tobacco. These novel models will be used to test the hypothesis that targeting the ATR DNA damage response pathway and programmed cell death protein 1 (PD- 1) immune checkpoint with concomitant radiation therapy will improve local and distant control of head and neck cancer. This research will establish a preclinical platform for improving understanding of head and neck cancer biology and for evaluating new therapeutic combinations with radiation therapy for this difficult to treat disease.